The clinical utility of many potential anti-cancer compounds is limited by undesired toxicity against non-target cells. Undesired toxicity in a drug is typically due to a lack of specificity, either in target tissue or in mechanism of action. If the drug target is present in normal as well as diseased tissues, then normal tissue as well as diseased tissue may be affected by the drug. The drug may also have multiple mechanisms of toxicity, one specific for diseased cells and the other non-specific. In either instance, there is often a dose-dependent difference in the actions of drugs against normal and diseased tissues, with the effects on diseased tissues being observed at lower concentrations than the effects on normal tissues. A major task of anti-cancer therapy is thus to determine the dosage at which the drug is therapeutically effective with minimal effects on normal tissues.
Phase I clinical trials are typically used to determine the maximum tolerated dose (MTD) of a potential anti-cancer compound, i.e., the maximum dose that can be safely administered without incurring toxicity. The difference between the MTD and the therapeutically effective dose is known as the therapeutic window. For a large number of anti-cancer agents, the MTD is very close to the therapeutically effective dose, i.e., the therapeutic window is very small. The MTD may even be lower than the therapeutically effective dose, making the agent unusable in the clinic.
Clinical anti-cancer therapy often involves attempting to achieve a delicate balance between effectiveness and undesired toxicity. Agents which synergize the action of a drug against diseased tissues while not affecting the toxicity against normal tissues could allow the effective use of doses of drug well below the MTD, thus increasing the therapeutic window and enhancing the safety and effectiveness of the therapy.
Geldanamycin (FIG. 1) is a benzoquinone ansamycin polyketide isolated from Streptomyces geldanus. Although originally discovered by screening microbial extracts for antibacterial and antiviral activity, geldanamycin was later found to be cytotoxic to certain tumor cells in vitro and to reverse the morphology of cells transformed by the Rous sarcoma virus to a normal state.
Geldanamycin's nanomolar potency and apparent specificity for aberrant protein kinase dependent tumor cells, as well as the discovery that its primary target in mammalian cells is the ubiquitous Hsp90 protein chaperone, has stimulated interest in the development of this anti-cancer drug. However, the association of hepatotoxicity with the administration of geldanamycin led to its withdrawal from Phase I clinical trials. As with several other promising anticancer agents, geldanamycin also has poor water solubility that makes it difficult to deliver in therapeutically effective doses.
More recently, attention has focused on 17-amino derivatives of geldanamycin, in particular 17-(allylamino)-17-desmethoxygeldanamycin (17-AAG; FIG. 1), that show reduced hepatotoxicity while maintaining Hsp90 binding. Certain 17-amino derivatives of geldanamycin, 11-oxogeldanamycin, and 5,6-dihydrogeldanamycin, are disclosed in U.S. Pat. Nos. 4,261,989; 5,387,584; and 5,932,566, each of which is incorporated herein by reference. Like geldanamycin, 17-AAG has limited aqueous solubility. This property requires the use of a solubilizing carrier, most commonly Cremophore® (BASF Aktiengesellschaft), a polyethoxylated castor oil which can result in serious side reactions in some patients.
Treatment of cancer cells with geldanamycin or 17-AAG causes a retinoblastoma protein-dependent G1 block, mediated by down-regulation of the induction pathways for cyclin D-cyclin dependent cdk4 and cdk6 protein kinase activity. Cell cycle arrest is followed by differentiation and apoptosis. G1 progression is unaffected by geldanamycin or 17-AAG in cells with mutated retinoblastoma protein; these cells undergo cell cycle arrest after mitosis, again followed by apoptosis.
The mechanism of action of benzoquinone ansamycins appears to be via binding to Hsp90 and subsequent degradation of Hsp90-associated client proteins. Among the most sensitive client protein targets of the benzoquinone ansamycins are the Her kinases (also known as ErbB), Raf, Met tyrosine kinase, and the steroid receptors. Hsp90 is also involved in the cellular response to stress, including heat, radiation, and toxins. Certain benzoquinone ansamycins, such as 17-AAG, have thus been studied to determine their interaction with cytotoxins that do not target Hsp90 client proteins.
U.S. Pat. Nos. 6,245,759; 6,306,874; and 6,313,138, each of which is incorporated herein by reference, disclose compositions comprising certain tyrosine kinase inhibitors together with 17-AAG and methods for treating cancer with such compositions. Münster et al., “Modulation of Hsp90 function by ansamycins sensitizes breast cancer cells to chemotherapy-induced apoptosis in an RB- and schedule-dependent manner,” Clinical Cancer Research (2001) 7: 2228-2236, discloses that 17-AAG sensitizes cells in culture to the cytotoxic effects of paclitaxel and doxorubicin. The Münster reference further discloses that the sensitization towards paclitaxel by 17-AAG is schedule-dependent in retinoblastoma protein-producing cells due to the action of these two drugs at different stages of the cell cycle: treatment of cells with a combination of paclitaxel and 17-AAG is reported to give synergistic apoptosis, while pretreatment of cells with 17-AAG followed by treatment with paclitaxel is reported to result in abrogation of apoptosis. Treatment of cells with paclitaxel followed by treatment with 17-AAG 4 hours later is reported to show a synergistic effect similar to coincident treatment.
Citri et al., “Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer chemotherapy,” EMBO Journal (2002) 21: 2407-2417, discloses an additive effect upon co-administration of geldanamycin and an irreversible protein kinase inhibitor, CI-1033, on growth of ErbB2-expressing cancer cells in vitro. In contrast, an antagonistic effect of CI-1033 and an anti-ErbB2 antibody, Herceptin, is disclosed.
Thus, while there has been a great deal of research interest in the benzoquinone ansamycins, particularly geldanamycin and 17-AAG, there remains a need for effective therapeutic regimens to treat cancer or other diseases or conditions characterized by undesired cellular hyperproliferation using such compounds, whether alone or in combination with other agents. If water-soluble benzoquinone ansamycins were available, such compounds might be more readily formulated and more effective in clinical treatment without dangerous hepatotoxicity. If effective therapeutic treatment regimens were available for administering the benzoquinone ansamycins with other proven anti-cancer compounds, there could be new and more effective means of treating cancer. If the potential of using a benzoquinone ansamycin to lower the effective dose of another anti-cancer agent could be realized, then not only could less expensive therapies be made available (since less drug would need to be administered) but also, and more importantly, one could use drugs that have previously not been useful in chemotherapy due to their narrow therapeutic window. Thus, there is an unmet need for synergists of anti-cancer compounds that allow for administration of doses significantly below the maximum tolerated dose while maintaining therapeutic effectiveness, along with appropriate dosing schedules for combination therapy. The present invention meets such needs in that it provides novel benzoquinone ansamycins and provides methods for using these novel compounds as well as known compounds in single-agent and combination therapies for the treatment of cancer and other diseases or conditions characterized by undesired cellular hyperproliferation.